Drug products are currently designed for three groups of individuals: infants, pediatrics, and adults. The needs of infants are different from those of children 2 to 12 years of age, and the needs of children are different from those of adults. Moreover, the needs of the elderly population are different than those of other adults. Another category of individuals needing an alternative drug delivery form are patients with chronic dosage regimens. Repeated dosing of tablets or pills may become problematic for patients having a need for daily dosage regimens. Thus, an alternative dosage form is needed for a variety of patient populations.
Pediatric patients have difficulty swallowing until they reach the age of about 10-16 years old. Younger pediatric patients generally take either chewable tablets, crush and mix regular tablets with food/juice, or take a liquid dosage form. Chewable tablets, generally a good dosage form, do not always sufficiently mask the taste of the active agent. Crushing and mixing regular tablets with food or juice is time-consuming, messy, and not always practical. The difficulty of liquid dosage forms, e.g., syrups, is that they are bulky, do not always taste good, and can be unstable as compared to a solid dosage form, such as a tablet. A practical and new dosage form would be of value for these patients.
With advancements in medical science and the focus on healthy lifestyles, there is projected growth of the elderly population in the U.S. and abroad. Currently, the U.S. population of persons 65 years of age or older receives nearly 30% of the medications prescribed. Moreover, it is anticipated that there may be a rise in the demand for drugs by the elderly. In spite of the disproportionately large demand for prescription pharmaceuticals among the elderly, relatively little attention has been directed to meeting the unique pharmacotherapeutic needs of this age group.
Many older patients experience difficulty in swallowing tablets or capsules and yet the vast majority of dosage forms administered to the elderly are tablets or capsules. Uncoated tablets are convenient and economical to manufacture but are often difficult to swallow and frequently cause discomfort by “hanging” in the throat. Coated tablets and capsules are somewhat easier to swallow but with increasing age and the large number of drug products that are administered to a single individual, this is a source of apprehension. Liquid dosage forms are relatively easy to administer but are more costly, easily spilled, often do not taste good, occupy large volumes of space per dosage unit, and possess stability problems.
Relative to solid oral dosage forms, liquid formulations have the distinct advantages of dosage flexibility and ease of swallowing. A unit dosage equivalent to that of several capsules or tablets may be administered in as little as a single volume of liquid. Moreover, there is a recognized need for formulations to be available in a convenient, easy-to-take liquid dosage form. However, prior art formulations of liquid oral suspensions that provide chemical stability, and thus, commercially sufficient shelf life for water-sensitive therapeutic agents in aqueous formulations have met with only limited success to date. Commercially viable liquid products, especially aqueous liquid products, will need to maintain the stability of therapeutic agents present in liquid dispersal systems, provide comparable or improved release profiles from the dispersed phase at the point of the therapeutic agent's absorption, and limit free drug concentration in the dispersion medium.
The difficulties surrounding the formulation of water sensitive therapeutic agents are well known. Generally, the contacting of moisture or water adversely affects one or more chemical properties or functionality of the agent that are at least in part important to the agent's therapeutic efficacy. For example, aspirin (acetylsalicylic acid) is probably the most widely used drug in the world, but its sensitivity to water and concomitant ester hydrolysis has limited the manner in which aspirin may be administered to a patient. The hydrolysis of acetylsalicylic acid in the presence of water to salicylic acid and acetic acid occurs relatively quickly. Several other impurities form during hydrolysis have been reported including acetylsalicylic anhydride and acetylsalicylosalicylic acid. The decomposition of aspirin by water is said to result in a major loss of its pharmacological activity. This decomposition has tended to limit the marketing of acetylsalicylic acid to solid preparation forms, especially with regard to preparations useful for myocardial infarction prophylaxis. As a rule, solid aspirin preparations may only be administered orally with rapid decomposition/hydrolysis taking place primarily in the acidic environment of the stomach, during the absorption in the gastric mucuous membrane and the liver. It has been reported that oral administration leads to a situation where about half of the acetylsalicylic acid will reach the blood stream in its hydroyzed form (Burghart, U.S. Pat. No. 6,306,843). The hydrolysis product (salicylic acid) formed during aspirin's absorption by a patient is indicated as a contributor to side effects such as, e.g., gastric hemorrhage; and the overdosages required because of aspirin's rapid degradation during absorption constitute a considerable additional burden to patients.
Some researchers have attempted to stabilize water sensitive therapeutic compounds to hydrolysis. For example, Galat (U.S. Pat. No. 5,776,431) discloses certain solid compositions of aspirin in combination with certain alkaline compounds that are reportedly stable to hydrolysis as their powder forms as compared to other prior art solid compositions showing instability to water of hydration. Galat also reported that his solid compositions are soluble in water, but he failed to test or mention whether his compositions were stable in aqueous media over time.
Others have attempted to reduce hydrolysis in solid compositions by coating or encapsulating the therapeutic agents. For example, Burgguiere et al. (U.S. Pat. No. 5,846,566) disclose certain coated aspirin particles wherein the coating agent consists of a coating composition comprising: at least one film-forming polymer insoluble in the gastrointestinal environment, at least one water-soluble polymer, at least one solid lubricating filler, and at least one hydrophobic plasticizer. Vachon and Nairn (J. Microencapsulation, 14(3), 281-301, 1997) describe the preparation of some aspirin microspheres prepared from certain acrylic polymers in non-aqueous solution as well as aspirin release from the microspheres over a 24 hour period.
Others have suggested the use of matrices for therapeutic agent delivery. For example, Malmsten (Soft Matter 2, 760-769, 2000) generally discloses the use of soft drug delivery systems including polymer and/or polysaccharide gels to provide patients with therapeutics.
Harel (US 2008/0044481) discloses certain microbeads containing oil-associated biologically active compounds and methods for their manufacture and use. The microbeads consist of a soluble complex of non-digestible polymer and emulsifier with oil-associated biologically active compounds embedded in a matrix of digestible polymer.
Agnihotri (European J. Pharmaceutics and Biopharmaceutics 63, 249-261 (2006)) studied the controlled release of cephalexin through gellan gum beads based on certain formulation parameters such as pH, therapeutic agent loading, in the presence of a particular mixture of calcium and zinc counterions.
Kedzierewicz et al.(Int. J. Pharmaceutics, 178, 129-136 1999) disclosed the preparation and release of a hydrophilic, water stable therapeutic agent, propranolol hydrochloride, from certain gellan gum beads.
McGurk et al. (U.S. Pat. No. 7,713,551) disclosed solid or semi-solid gelatin nanoparticulate active agent dosage forms comprising at least one nanoparticulate active agent composition and at least one gel forming substance which exhibits gelation sufficient to retain excess water in the solid or semi-solid gelatin form. The agent composition is said to require at least one active agent of certain particle size and at least one surface stabilizer adsorbed on or associated with the surface of the active agent. These dosage forms reportedly have the advantage of easy administration combined with rapid dissolution of the active agent following administration.
Attempts to eliminate hydrolysis of water sensitive therapeutic agents by merely employing non-aqueous liquids as delivery vehicles has met with limited success. For example, Burghart (U.S. Pat. No. 6,306,843) mentioned certain prior art stable acetylsalicylic acid solutions in pharmaceutically acceptable non-aqueous organic solvents such as e.g., propylene glycol, ethyl alcohol, glycerin or polyethylene glycol, that were prepared in an attempt to avoid hydrolysis of water sensitive compounds. He reported that even in these solvents, traces of moisture and accompanying de-esterification cannot be fully eliminated.
Hollenbeck (US 2006/0134148) discloses certain aqueous suspensions of drug delivery systems that comprise beads containing water soluble drugs that are coated with a material capable of controlling release of the highly soluble drug and immersed in an aqueous dispersion medium. In addition, products utilizing the Hollenbeck drug delivery systems reportedly have a long shelf life since the drug remains confined in the dispersed phase and any functional coatings remain intact. These compositions are said to comprise:
(a) a dispersed phase comprising an ion-exchange matrix drug complex comprising a pharmaceutically acceptable ion-exchange matrix and a water-soluble electrolytic drug associated with the ion-exchange matrix, wherein the surface charge of the ion-exchange matrix is opposite that of the electrolytic drug and a non-electrolytic, soluble, low molecular weight excipient; and
(b) a dispersion medium.
Livney (2011/0038942) discloses certain colloidally stable dispersions of nanoparticles comprising beta-lactoglobulin and a polysaccharide which are transparent when diluted in aqueous media that are reportedly useful as, inter alia, delivery vehicles of hydrophobic nutraceuticals and fat-soluble vitamins.
Lee (US 2009/0104251) discloses reportedly heat stable microcapsule compositions that may include a protein, a polyanionic polymer, and a taste masking agent. Lee further discloses encapsulates that may include a protein and gellan gum.
Yokoyama, Hideakira et al (US 20050089577) disclose certain liquid matrices that reportedly undergo phase transfer in vivo and liquid oral preparations in which medicine can be easily solubilized, dispersed or suspended and swallowed. The liquid matrices are said to have favorable working properties in sterilization and a high stability because of their liquid nature. Yokoyama indicates that the matrices also exhibit an effect of masking bitterness, and gels in vivo so as to control the release speed of the medicine.
It would further be beneficial to achieve ease of administration with a drug delivery system exhibiting sufficient stability and/or bioavailability targeting young, older, and/or chronic dosage patients, especially those systems that are palatable to the targeted groups. Prior art gelatin dosage forms have been unable to solve this dual necessity of bioavailability in combination with active agent stability.
Previous liquid formulations, including for example, nanosol formulations may require a solvent to initially solubilize poorly soluble therapeutic agent in the matrix only to evaporate it subsequently. Alternatively the pH of of the matrix is adjusted to better dissolve the therapeutic. Such solubilization of an active agent is disclosed as undesirable, as solubilization may affect the various properties of the active agent, such as the solidification state of the active agent (i.e., whether the active agent is in an amorphous or crystalline form), stability of the active agent in the aqueous state, how much of the active agent has returned to the solid state, etc. See McGurk et al., U.S. Pat. No. 7,713,551. Moreover, solubilization of an active agent can change the active agent's pharmacological and pharmacokinetic characteristics.
Another drawback to certain of these formulation systems is that they does not retain excess water, which is essential for effective redispersability, and hence any dosage forms employing such formulations may exhibit poor pharmaceutical bioavailability. While the stability (e.g., water sensitivity) of therapeutic agents present in liquid dispersal systems, their release profiles from the dispersed phase, and their free drug concentration in the dispersion medium are all important for commercial success, their palatability to the consumer also factors into their degree of market acceptance. Therapeutic agents often carry a bitter taste profile that makes them unpalatable without masking. The bitter taste profile also can extend to a range of other pharmaceutical composition components, food and beverage ingredients and bulking agents, further complicating an agent's formulation. The desire for improved palatability in products including one or more of these moieties, especially in applications where the products are administered to pediatric patients, has prompted research efforts to reduce the impact of bitterness for end users. Overcoming bitter taste profiles in pharmaceuticals is especially problematic in liquid dose formulations. To be reasonably effective, the taste masking agent and therapeutic should preferably have similar physical properties, so that they act similarly with receptors and/or behave similarly in devised containment systems with regard to solubility and or leaching for example. Among common methods for achieving taste masking in solid oral compositions are included the use of flavor enhancers, polymer coatings, inclusion complex formation with cyclodextrin, use of ion exchange resins, solubility limiting methods, liposome, multiple emulsions, use of anesthetic agents, etc. See Ettner et al., “Reducing the Bitterness of Drugs,” Pharmaceutical Formulation & Quality, September 2006.
Miyazaki et al. (Int. J. Pharmaceutics 297, 38-49 (2005) reported on the effect of certain polyhydric alcohol taste masking agents on in situ gelling pectin formulations for oral sustained delivery of acetaminophen and ambroxol. Pectin sols containing certain therapeutics reportedly gelled in situ in rat stomachs allowing assessment of bioavailability and sustained release of the therapeutic from the gel.
Prior art researchers have considered cyclodextrins for their potential to act as bitter taste masking agents in oral drug delivery. (See J. Szejtli et al., Euro. J. Pharmaceutics and Biopharmaceutics, 61, 115-125, 2005). In addition to taste masking ability, researchers have reported that cyclodextrins may help to improve drug bioavailability by increasing drug solubility, increase the rate of dissolution and stability of drug at its absorption site and/or in formulation, and/or reduce drug induced irritation (See, for example, Pandya, J., “Compatible Polymer used as Characterization Services Size complexes in various drug delivery systems,” submitted Mar. 1, 2008 to Pharminfo.net.
Cyclodextrins are typically introduced in one of two ways into pharmaceutical compositions to assist in bitterness masking. In some instances preformed complexes or clathrates of therapeutics are employed in the compositions. However, Friesen stated that an inherent drawback of this approach is that incorporation of a pre-formed drug:cyclodextrin complex into a dosage form requires that the complex be prepared, isolated and purified. (See Friesen et al., US Patent Publication 2008/0075784). Alternatively, some therapeutics may be dry blended with cyclodextrins and added to the pharmaceutical composition as a physical mixture rather than a pre-formed complex. This approach can also have drawbacks. To demonstrate this point, some physical mixtures (e.e., dry blended) of unpleasant tasting drugs and cyclodextrin do not provide adequate taste masking. For example, a simple blend of cetirizine and beta-cyclodextrin reportedly still results in the bitter taste of cetirizine being tasted almost immediately. (See Friesen et al. US Patent Publication 2008/0075784).
Alternatively, Fanarra, US 2002/0032217 A1, discloses pre-forming (rather than blending the cyclodextrin and cetirizine) the drug:cyclodextrin complex and subsequently incorporating the pre-formed complex into dosage forms. Fanarra discloses forming solutions of cetirizine and beta-cyclodextrin that had reduced bitter taste due to the pre-formation of a drug:cyclodextrin complex.
While cyclodextrins have been used in pharmaceutical applications, Hladon reported an increase in the stability of an ibuprofen/beta-cyclodextrin complex at elevated temperature over time as compared to the non-complexed therapeutic agent (See Hladon et al. (J. Inclusion Phenomena and Macrocyclic Chemistry 36, 1-8, 2000)). Other reports have many compounds for which cyclodextrin complexation presents disadvantages which render them unsuitable for pharmaceutical use. See J. Szejtli, Pharmaceutical Technology, 1991, 24 38; and U.S. Pat. No. 5,362,860. Consequently, beneficial and/or adverse effects on multiple properties should be considered. For example, Tee and Takasaki (Can. J. Chem. 63, 3540-3544 1985) reviewed the stability of the water sensitive therapeutic, aspirin, when complexed with cyclodextrin and concluded that while the solubility of aspirin in aqueous solution may be enhanced through the use of the alpha-, and beta-cyclodextrin complexing agents, “any attempts to use these for pharmaceutical purposes should take into account the ability of cyclodextrins to promote the deacetylation of aspirin in aqueous solution.” (See Tee and Takasaki at page 3540). Thus, in some situations, while one or more properties such as bioavailability may be improved through the use of cyclodextrin complexes alone, others such as shelf stability, efficacy, and/or the potential for increased side effects may be inadvertently adversely affected by the use of these same cyclodextrins.
It would be advantageous to provide water stable pharmaceutical compositions and liquid dosage forms derived therefrom employing therapeutic agents that minimize the effect of water on the therapeutic agents or their mode of action. This is especially true for water sensitive therapeutic agents, where hydrolysis, especially during shelf storage, and in particular in aqueous drug delivery systems, may lead to the production of by-products that reduce overall efficacy and/or increase side effects.
Additionally, there is a need for water stable pharmaceutical compositions and shelf stable aqueous liquid dosage forms derived therefrom that are not only easier to orally ingest than tablets for patients but are palatable to the taste. In certain areas of the world where water quality limits the ability to provide such water sensitive therapeutic agents in aqueous solution, it may be useful to further provide compositions and/or liquid dosage forms of these agents that may be safely ingested. As such, the ability to prepare these therapeutic compositions in the appropriate dosages in advance at locations far removed, where water quality in not an issue, would facilitate treatment of those affected by certain diseases, disorders, or conditions. It remains a challenge to achieve pharmaceutically acceptable suspension liquid dosage forms containing a pharmaceutically active ingredient in the dispersed phase, having a low free drug concentration in the dispersion medium, and capable of providing immediate or sustained drug release from the dispersed phase after administration to a patient. Improvements that would allow manufacturers to provide pre-formed drug:cyclodextrin complexes into a dosage form without the necessity that the complex be isolated and purified are also desirable. The present invention is directed to these and other important ends.